Smokers are the largest population exposed to known carcinogens. Besides containing carcinogenic agents such as the tobacco-specific nitrosamines [TSNA, e.g., 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone, (NNK)], the polycyclic aromatic hydrocarbons [e.g., benzo[a]pyrene, (BaP))] and benzene, cigarette smoke is also a rich source of free radical species that are capable of inducing oxidative stress. Free radicals represent a serious threat to cellular components. Although significant progress has been made toward explaining the causal association of cigarette smoking and cancers, several important academic and cancer control issues remain to be addressed. This Program consists of 4 Projects and a CORE. In contrast to extensively studied genotoxic agents, such as NNK and B[a]P, there is a lack of information on the molecular mechanisms by which reactive oxidative species (RO2)- induced oxidative damage occurs in vivo. Thus, Project 1 will test the hypothesis that an inflammatory response to cigarette smoke in the guinea pig respiratory system contributes to the tumor promotion phase of lung carcinogenesis by inhibiting apoptosis through pathways involving activation of the transcriptional nuclear factor-Kappa B (NF-kappaB) and activator protein-1 (AP-1) and that this process can be modulated by dietary anti-oxidants (vitamins and EGCG, a polyphenolic compound in tea). The results should provide a strong rationale for dietary recommendations to smokers who are unable to quit. The molecular mechanisms responsible for the induction of bone marrow toxicity and leukemia by benzene remain to be defined. Thus, in model studies, Project 2 will test the hypothesis that a superoxide, generated via redox cycling of ring-hydroxylated derivatives of benzene, reacts with nitric oxide to form peroxynitrite; the latter may be responsible for the toxicity of benzene and tobacco-associated leukemia in smokers. Project 3 combines the most sensitive analytical tools with molecular and clinical investigations to test the hypothesis that critical events required for the development of cervical cancer are genetic damage and mutations of p53 induced by tobacco carcinogens combined with HPV-induced deactivation of p53 and inhibition of apoptosis. Primary prevention techniques must continue to take a prominent role in our efforts to reduce tobacco-related cancers. However, such efforts showed limited success in the past and, chemopreventive approaches can provide complementary strategies. One of the most exciting clinical trials in the U.S.A. is the recent study demonstrating that supplementation of human nutrition with selenium-enriched yeast significantly reduces lung cancer incidence and mortality. The chemopreventive efficacy depends on the structure of the selenium-containing compound; not the element per se. Thus, Project 4 will test the hypothesis that selenium may, in part, inhibit lung carcinogenesis by inhibiting NF-kappaB; thereby down-regulating COX- 2 and LOX activities and inducing apoptosis. In summary, this Program Project proposes to resolve critical problems in tobacco carcinogenesis and provide insights into mechanisms and optimal models of intervention by modulation of smoke carcinogens and by nutritional supplements, i.e., selenium compounds, vitamins, and EGCG.